Cancer
Despite many years of research, there exists a compelling need to develop new and more effective therapeutic strategies for cancer. The use of many agents used in cancer treatment is limited because of their cytotoxic effects on normal tissues and cells. This is a particular concern for agents that kill cells by damaging DNA and/or inhibiting DNA replication.
Retinoids
Retinoids are a group of natural and synthetic analogues of vitamin A. All-trans-retinoic acid (ATRA), the biologically most active metabolite of vitamin A plays a major role in regulating cellular growth and differentiation.i Since retinoids are capable of inhibiting growth, inducing terminal differentiation and apoptosis in cultured cancer cell lines, there is a wide interest in their use in cancer therapy.ii The biological effects of retinoids result from modulation of gene expression, mediated through two complex types of nuclear receptors, retinoic acid receptors, and retinoid X receptors (RARs and RXRs).iii Each type includes 3 distinct subtypes (α, β, and γ) encoded by distinct genes. Each RAR and RXR subtype is expressed in specific patterns in different tissues and is thought to have a specific profile of gene-regulating activity. The nuclear receptors function as dimers. RARs form heterodimers with RXRs. RXRs are more versatile, binding to RARs and other nuclear receptors, including thyroid hormone receptors and vitamin D receptors. Therefore, ATRA and other retinoids, through a variety of mechanisms, can modulate the expression of an extraordinarily large number of genes.iv 
One of the most impressive effects of retinoids is on acute promyelocytic leukemia (APL). Treatment of APL patients with high doses of ATRA results in most of the cases in complete remission (Castaigne et al., 1990). Other research has been conducted on retinoid-based therapies for other cancers.v 
Exogenous application of retinoids such as ATRA inhibits the growth and induces apoptosis in prostate cancer cell lines. Pasquali et al showed that the concentration of ATRA was 5-8 times lower in prostate carcinoma tissue compared with normal prostate and benign prostate hyperplasia.vi In vivo studies showed that ATRA inhibited induction and caused the disappearance of prostate tumors in animals.vii In spite of these encouraging results, the effects of ATRA therapy on human prostate cancer in the clinic have been disappointing.
One of the causes of the scarce therapeutic effects seems to be the rapid in vivo metabolism of ATRA into inactive metabolites.viii The inhibition of cytochrome P450 mediated ATRA metabolism by retinoic acid metabolism blocking agents (RAMBAs) is a promising approach in order to increase the levels of ATRA.ix Liarozole, the first RAMBA to undergo clinical investigations, was shown to increase ATRA levels in the tumor, resulting in anti-tumor activity.x Although, clinical development of this compound for prostate cancer therapy was discontinued for undisclosed reasons, it was recently approved in Europe and USA as an orphan drug for the treatment of congenital ichthyosis.xi 
PCA tumors that arise after anti-hormonal therapy generally are less differentiated. Differentiation therapy remains a promising therapeutic approach in the treatment and chemoprevention of a variety of cancers, including PCA. Among the differentiation agents, retinoids, rexinoids, retinoid-related molecules (RRIVIs) and histone deacetylase inhibitors (HDACIs) have shown promising biological activities as single agents in several preclinical studies of both hematological and solid malignancies.xii 
A goal of differentiation therapy is to induce malignant cells to pass the block to maturation by allowing them to progress to more differentiated cell types with less proliferative ability. Others have led the way in the discovery of agents that inhibit the enzyme histone deacetylase, thereby altering chromatin structure and changing gene expression patterns.xiii RAs exert their effects via a nuclear receptor complex that interacts with promoters of RA-responsive genes.xiv 
Applicants have reported on a family of compounds that inhibit the P450 enzyme(s) responsible for the metabolism of all-trans retinoic acid (ATRA).xv These compounds, also referred to as retinoic acid metabolism blocking agents (RAMBAs), are able to enhance the antiproliferative effects of ATRA in breast and prostate cancer cells in vitro.xvi In addition, the RAMBAs were shown to induce differentiation and apoptosis in these cancer cell lines. Applicants' observed that the breast cancer cell lines were exquisitely more sensitive to the RAMBAs.xvii 
By introduction of nucleophilic ligand at C-4 of ATRA or 13-CRA, and modification of the terminal carboxylic acid group, Applicants invented a series of potent RAMBAs some of which are by far the most potent retinoic acid metabolism inhibitors known.xviii xix See U.S. Pat. No. 7,265,143, which is hereby incorporated by reference in its entirety.
Applicants also demonstrated that these RAMBAs inhibited the growth of several breast and prostate cancer cell lines and could exquisitely enhance the ATRA-mediated antiproliferative activity in vitro and in vivo.xx xxi xxii It was shown that VN/14-1 binds and activates the RARα,β,γ receptors, albeit it is significantly less potent than ATRA. Furthermore, none of the RAMBAs showed significant binding to either cellular retinoic binding proteins (CRABP I or II).XXiii It has also been demonstrated that some RAMBAs inhibited the growth of established breast and prostate tumor xenografts and that their mechanisms of action may in part be due to induction of differentiation, apoptosis and cell cycle arrest.xxiv xxv xxvi xxvii 
Some of Applicants' proprietary RAMBAs appear to be the most potent ATRA metabolism inhibitors known.xxviii Furthermore, some of these proprietary RAMBAs also exhibit retinoidal and cell antiproliferative activities in a number of human cancer cell lines. These multiple biological activities have prompted Applicants to classify them as “atypical RAMBAs”.
The anti-neoplastic activities of RAMBAs may be cell type dependent. Applicants have shown that some RAMBAs (e.g., VN/14-1) are more effective in breast cancer cell lines while others (e.g., VN/66-1) are more effective in prostate cancer cell lines.xxix xxx xxxi xxxii 
The apparent lack of sensitivity of the breast cancer cells (MDA-MB-231) and two prostate cancer cell lines (LNCaP and PC-3) to ATRA and some of Applicants' proprietary RAMBAs may be due to the differential expressions of various genes that are essential for retinoid activity.
There continues to be an urgent need to develop new therapeutic agents with defined targets to prevent and treat cancer, including prostate and breast cancer.